GENETIC INFLUENCES ON ALCOHOLISM RISK : A REVIEW OF ADOPTION AND TWIN STUDIES

T National Institute on Alcohol Abuse and Alcoholism and the entire alcoholism com­ munity were deeply saddened by the death on August 12, 1995, of Mark Keller, professor emeritus of alcohol studies at Rutgers University and a pioneer in the field of alcohol research. Though principally self­taught, Mr. Keller’s motivation and inquisitiveness resulted in laud­ able academic achievements. He began his career in alcohol­related research and teaching in the mid­1930’s at the New York University School o f M e d i c i n e . I n t h e e a r l y 1 9 4 0 ’ s , a t Y a l e University, he helped found the first Center of Alcohol Studies. He and the Center then moved to Rutgers University in 1962. There, Mr. Keller helped develop the Center’s unique library, which continues to be one of the most complete alcohol­relevant research and refer­ ence libraries in the world. He also shared his extensive know­ ledge of the field through lectures at Brandeis University. Mr. Keller’s more than 200 publications are testament to his lifelong commitment to bringing order to the field of alcohol re­ search, as evidenced by his text, the Dictionary of Words about Alcohol. He also edited the International Bibliography of Studies on Alcohol and was editor of the first and second volumes of the Special Report to the U.S. Congress on Alcohol and Health. For the better part of 50 years, as editor and, later, as editor emeritus, he supported and guided the publication of the Journal of Studies on Alcohol. After his official retire­ ment, Mr. Keller continued to pursue his work as a scholar and lecturer, and he re­ cently was studying interpretations of the historical aspects of the Biblical texts. In 1991 Mr. Keller coauthored an article for Alcohol Health & Research World on defining alcoholism. In an interview in that issue, Mr. Keller was asked how he viewed the future of alcohol research. He responded, “I’m an opti­ mist. My long­range outlook about the field is that gradually, as the result of research, we will learn more and more, and we’ll begin to learn how to prevent alcoholism.” Thanks to Mr. Keller’s dedication, scholarship, and the unique contributions he made to the field of alcohol­ ogy (Keller’s term), we are that much closer to realizing this goal.


TRIBUTE TO MARK KELLER
T he National Institute on Alcohol Abuse and Alcoholism and the entire alcoholism com munity were deeply saddened by the death on August 12, 1995, of Mark Keller, professor emeritus of alcohol studies at Rutgers University and a pioneer in the field of alcohol research.
Though principally selftaught, Mr. Keller's motivation and inquisitiveness resulted in laud able academic achievements. He began his career in alcoholrelated research and teaching in the mid1930's at the New York University School o f M e d i c i n e . I n t h e e a r l y 1 9 4 0 ' s , a t Y a l e University, he helped found the first Center of Alcohol Studies. He and the Center then moved to Rutgers University in 1962. There, Mr. Keller helped develop the Center's unique library, which continues to be one of the most complete alcoholrelevant research and refer ence libraries in the world. He also shared his extensive know ledge of the field through lectures at Brandeis University.
Mr. Keller's more than 200 publications are testament to his lifelong commitment to bringing order to the field of alcohol re search, as evidenced by his text, the Dictionary of Words about Alcohol. He also edited the International Bibliography of Studies on Alcohol and was editor of the first and second volumes of the Special Report to the U.S. Congress on Alcohol and Health. For the better part of 50 years, as editor and, later, as editor emeritus, he supported and guided the publication of the Journal of Studies on Alcohol. After his official retire ment, Mr. Keller continued to pursue his work as a scholar and lecturer, and he re cently was studying interpretations of the historical aspects of the Biblical texts.
In 1991 Mr. Keller coauthored an article for Alcohol Health & Research World on defining alcoholism. In an interview in that issue, Mr. Keller was asked how he viewed the future of alcohol research. He responded, "I'm an opti mist. My longrange outlook about the field is that gradually, as the result of research, we will learn more and more, and we'll begin to learn how to prevent alcoholism." Thanks to Mr. Keller's dedication, scholarship, and the unique contributions he made to the field of alcohol ogy (Keller's term), we are that much closer to realizing this goal.

GENETIC INFLUENCES ON ALCOHOLISM RISK: A REVIEW OF ADOPTION AND TWIN STUDIES
A doption and twin studies have long been used to study the re l a t i v e i m p o r t a n c e o f g e n e t i c a n d environmental influences on the devel opment of alcoholism. Dr. Andrew C. Heath recently completed a reanal ysis of this large body of literature. His research confirms the existence of a significant genetic influence on alco holism. Moreover, these genetic fac t o r s h a v e r e m a i n e d r e mark ab ly consistent over time, whether the com parison is of U.S. male twins born in the 1920's or U.S. adoptees born in the 1940 's, 1950's, and 1960's;

A LONGTERM STUDY OF SONS OF ALCOHOLICS
A classic approach to examining genetic factors in alcoholism has been to study alcoholic fathers and their sons. In this article, Dr. Marc A. Schuckit reviews data from a series of studies spanning 25 years. These longterm studies are proving espe cially useful for identifying specific alcoholrelated traits that might inter act with the environment to increase a person's risk for developing alco hol problems. Dr. Schuckit describes the most recent results, comparing men with family histories of alco holism and those with no such histo r i e s . A m a j o r f i n d i n g f r o m t h i s research is that young men who had low responses to alcohol (i.e., who required more alcohol to experience an effect) had higher rates of alcohol problems later in life, regardless of their family histories. (pp. 172-175)

THE SEARCH FOR BIOCHEMICAL MARKERS
G enetically determined biochemi cal markers of alcoholism could help researchers and treatment pro viders identify people who are predis posed to alcoholism. Such markers would improve prevention, diagnosis, and treatment efforts as well as facil itate research into the genetic basis of alcoholism. Two markers now under investigation are the activity levels of the enzymes monoamine oxygenase and adenylyl cyclase. These markers are inherited and frequently are lower in alcohol ic than i n n o n alcohol ic subjects. Although the activity levels of these enzymes cannot be used to distinguish the entire spectrum of al coholics, Drs. Robert M. Anthenelli and Boris Tabakoff report that the markers may be useful in defining certain subtypes of alcoholics. (pp. 176-181)

GENETIC INFLUENCES AFFECTING ALCOHOL USE AMONG ASIANS
T he body processes alcohol using two important enzymes, alcohol dehydrogenase and aldehyde dehy drogenase, both of which are geneti cally controlled. Impaired function of these enzymes can strongly affect how a person feels when he or she consumes alcohol. For example, people with a defective aldehyde dehydro genase gene respond to alcohol con sumption with intense flushing and other physical symptoms, such as nausea. Because of the unpleasant side effects, these people generally consume less alcohol and are at a lower risk for developing alcoholism than people with functional genes. People of Asian heritage are more likely to have a defect in the aldehyde dehydrogenase gene than are those of other ethnic groups. Drs. Tamara L. Wall and Cindy L. Ehlers review studies of Asian subjects showing that people who inherit the defective gene from one or both parents have different physiological, psychological, and electrophysiological responses to alcohol than do people who have the functional gene. (pp. 184-189)

THE HUMAN GENOME PROJECT
N early all human diseases, in c l u d i n g a l c o h o l i s m , c a n b e traced, at least in part, to alterations in one or more genes. Thus, identifying and understanding all the genes that specify the body's functions could provide scientists with powerful tools with which to understand, prevent, and treat diseases. An international re search effort, the Human Genome Project, is now under way to decipher the chemical makeup of the entire hu man genetic code (i.e., the genome), to isolate all its genes, and to analyze the genes' functions. Dr. Francis S. Collins and Leslie Fink summarize the project's goals and recent pro gress. Although the project still is far from completion, researchers already have reached important milestones. The stage is now set for identifying the tens of thousands of remaining human genes and for using the newly gained knowledge in ways that are both responsible and ethical. (pp. 190-195) ADOPTION STUDIES S ince the beginning of this century, researchers have studied children who were separated from their bio logical families and raised in adop tive homes to determine the effects of genetic and environmental factors on certain characteristics, such as in telligence. According to Dr. Remi J. Cadoret, adoption studies are espe cially useful for assessing the rela t i v e c o n t r i b u t i o n s o f g e n e s , t h e environment, and geneenvironment interactions in the development of alcoholism. Despite the significant impact that adoption studies have h a d o n o u r u n d e r s t a n d i n g o f t h e causes of alcohol dependence, Dr. Cadoret notes that confounding envi ronmental factors, such as selective placement-in which children are preferentially placed in traditional, wellestablished, twoparent homes-can limit the usefulness of such stud ies if researchers fail to give such variables adequate consideration. (pp. 195-200) TWIN STUDY DESIGN T wins offer a unique resource for evaluating the genetic aspects of behavior. Twins may be either identi cal, and thereby have the same genet ic information, or fraternal, with only a portion of their genetic makeup in common. When a certain behavior or trait, such as alcoholism, is shared by both twins, it provides researchers with a unique opportunity for deter mining the degree to which that be h a v i o r i s l i n k e d t o a g e n e t i c influence. Drs. Carol A. Prescott and Kenneth S. Kendler describe how twin studies are conducted. They also review findings on the genetics of al coholism from studies of male, fe male, and oppositesex twin pairs. (pp. 200-205) GENETIC ENGINEERING IN ANIMAL MODELS W hat role do individual genes play in the predisposition to al cohol dependence? Thanks to genetic engineering techniques now being pi oneered in laboratory animals, re s ea r ch er s are m aking p ro g ress in identifying specific genes that con tribute to the development of alco h o l i s m i n h u m a n s . D r s . S u s a n n e HillerSturmhöfel, Barbara J. Bowers, and Jeanne M. Wehner describe the potential usefulness as well as the limit at i o n s of t ec h ni q ue s s uc h a s transgenic and knockout mice and antisense RNA strategies. Though the use of these technologies is still in its infancy in alcohol research, s t u d i e s f r o m o t h e r f i e l d s alr e ad y have shed light on several complex physiological processes, such as the way alcohol affects the body's re sponse to stress. (pp. 206-213)

PRIMATES IN ALCOHOL RESEARCH
H u m a n s a n d p r i m a t e s s h a r e a large percentage of their genetic material and often display comparable complex social behaviors. Because of these similarities, primates fre quently have been used to study hu man psychiatric syndromes. Only recently, however, have these ani mals appeared as subjects in alcohol research. In this article, Dr. J. Dee Higley reviews the use of nonhuman primates in alcohol research. He de scribes how this animal model of hu man behavior is providing insight into the genetic and environmental components that influence alcohol consumption and dependence. (pp. 213-216)

MOLECULAR BIOLOGY
A lthough family, twin, and adop tion studies have established a genetic contribution to alcoholism, the nature of this association is un known. To better identify the role of genetics in people who are predis posed to alcoholism, researchers are turning to molecular biology tech niques. In this article, Dr. Alison M. Goate describes the use of two such techniques. Positional cloning al lows researchers to identify genes l i n k ed t o s pe c i fi c d i s e as es ba s e d solely on their location within the s u b j e c t ' s g e n e t i c m a t e r i a l ( i . e . , genome). Actual genes implicated in the disease process (i.e., candidate genes) are then selected for analysis based on the positional cloning data. As the Human Genome Project con tinues to chart unknown sections of the genetic map, more diseaselinked genes will be identified using a com bination of positional cloning and the candidate gene approach. (pp. 217-220)

QUANTITATIVE TRAIT LOCI MAPPING
A lcoholism is thought to be influ enced by many genes located throughout the human genetic mate rial (i.e., the genome). These genes are linked to certain characteristics, or traits, that are believed to influ ence the body's responses to alcohol. Such traits are called quantitative be cause they are influenced by several genes; each gene, however, affects the overall characteristic to only a certain extent. Quantitative trait loci (QTL) analysis provides a means of locating and measuring the effects of a single QTL on a behavioral trait, such as alcoholism. In this article, Drs. Judith E. Grisel and John C. Crabbe provide a brief overview of the methods involved in QTL analy ses and include several exa mple s demonstrating the application of the technique. (pp. 220-227)

THE COLLABORATIVE STUDY ON THE GENETICS OF ALCOHOLISM
I n 1989 the National Institute on Alcohol Abuse and Alcoholism ini tiated the Collaborative Study on the Genetics of Alcoholism (COGA), a multidisciplinary, multicenter study to identify and analyze genetic fac tors contributing to a person's risk for alcoholism. In this special sec t i o n , s e n i o r C O G A i n v e s t i g a t o r s h i g h l i g h t p r e l i m i n a r y f i n d i n g s gleaned from the ambitious project. The authors describe the history and design of COGA, emphasize the im portance of accurate clinical assess ment of alcoholism, summarize data from neurophysiological and alcohol administration experiments, review r e s e a r c h p r o g r e s s r e g a r d i n g b i o c h e m i c a l a n d m o l e c u l a r g e n e t i c markers, and provide an overview of the data analysis approaches being used. (pp. 228-236) ALCOHOL'S EFFECTS ON GENE EXPRESSION N ot only does a person's genetic makeup help determine his or her response to alcohol consumption, alcohol, in turn, can alter the expres sion of certain genes. Scientists have developed several methods to isolate and identify such alcoholregulated genes. Dr. Michael F. Miles exam ines a few of these techniques and the genes scientists have helped to identify. These genes, which are in volved in a variety of physiological functions, such as cellular communi cation, could play a pivotal role in the brain' s adaptation to alcohol. Further study will enable scientists to better understand the mechanisms through which alcohol might modify the expression of these genes. (pp. 237-243)